sirolimus and Albuminuria

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high-risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy.

Topics: Albuminuria; Child; Cyclosporine; Diabetes Mellitus; Diabetic Retinopathy; Glucocorticoids; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Insulin; Liver Failure; Liver Transplantation; Metformin; Pediatrics; Risk Factors; Sirolimus; Tacrolimus

Nephrotic-range proteinuria has been known for years to be associated with poor renal outcome. Newer evidence indicates that early (1-3 months after transplantation) low-grade proteinuria and microalbuminuria (1) provide information on the graft in terms of donor characteristics and ischemia/reperfusion injury, (2) may occur before the development of donor-specific antibodies, (3) predict the development of diabetes and cardiovascular events, and (4) are associated with reduced long-term graft and patient survivals. Low-grade proteinuria and microalbuminuria are also predictive of diabetes, cardiovascular morbidity, and death in nontransplanted populations, which may help us to understand the pathophysiology of low-grade proteinuria or microalbuminuria in renal transplantation. The impact of immunosuppressive medications, including mammalian target of rapamycin inhibitors, on graft survival is still discussed, and the effect on proteinuria is crucial to the debate. The fact that chronic allograft rejection may exist as early as 3 months after renal transplantation indicates that optimal management of low-grade proteinuria or microalbuminuria should occur very early after transplantation to improve long-term renal function and the overall outcome of renal transplant recipients. The presence of low-grade proteinuria or microalbuminuria early after transplantation must be taken into account to choose adequate immunosuppressive and antihypertensive medications. Limited information exists regarding the benefit of therapeutic interventions to reduce low-grade proteinuria or microalbuminuria. Whether renin angiotensin blockade results in optimal nephroprotection in patients with low-grade proteinuria or microalbuminuria is not proven, especially in the absence of chronic allograft nephropathy. Observational studies and randomized clinical trials yield conflicting results. Finally, randomized clinical trials are urgently needed.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Prognosis; Proteinuria; Randomized Controlled Trials as Topic; Risk Factors; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; 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The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency.. In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria ≤0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline.. At the 1-year preplanned interim analysis, GFR fell from 26.7±5.8 to 21.3±6.3 ml/min per 1.73 m(2) (P<0.001) and from 29.6±5.6 to 24.9±6.2 ml/min per 1.73 m(2) (P<0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8±81.8 versus 154.9±152.9 μg/min; P=0.02) and proteinuria (0.3±0.2 versus 06±0.4 g/24 h; P<0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P<0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrast-enhanced computed tomography imaging) increased by 9.0% from 2857.7±1447.3 to 3094.6±1519.5 ml on sirolimus and 4.3% from 3123.4±1695.3 to 3222.6±1651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively.. Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.

Topics: Adult; Albuminuria; Disease Progression; Early Termination of Clinical Trials; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Sirolimus

In autosomal dominant polycystic kidney disease (ADPKD), aberrant activation of the mammalian target of rapamycin (mTOR) pathway is associated with progressive kidney enlargement. The drug sirolimus suppresses mTOR signaling.. In this 18-month, open-label, randomized, controlled trial, we sought to determine whether sirolimus halts the growth in kidney volume among patients with ADPKD. We randomly assigned 100 patients between the ages of 18 and 40 years to receive either sirolimus (target dose, 2 mg daily) or standard care. All patients had an estimated creatinine clearance of at least 70 ml per minute. Serial magnetic resonance imaging was performed to measure the volume of polycystic kidneys. The primary outcome was total kidney volume at 18 months on blinded assessment. Secondary outcomes were the glomerular filtration rate and urinary albumin excretion rate at 18 months.. At randomization, the median total kidney volume was 907 cm3 (interquartile range, 577 to 1330) in the sirolimus group and 1003 cm3 (interquartile range, 574 to 1422) in the control group. The median increase over the 18-month period was 99 cm3 (interquartile range, 43 to 173) in the sirolimus group and 97 cm3 (interquartile range, 37 to 181) in the control group. At 18 months, the median total kidney volume in the sirolimus group was 102% of that in the control group (95% confidence interval, 99 to 105; P=0.26). The glomerular filtration rate did not differ significantly between the two groups; however, the urinary albumin excretion rate was higher in the sirolimus group.. In adults with ADPKD and early chronic kidney disease, 18 months of treatment with sirolimus did not halt polycystic kidney growth. (Funded by Wyeth and others; ClinicalTrials.gov number, NCT00346918.)

Topics: Adult; Albuminuria; Creatinine; Disease Progression; Female; Glomerular Filtration Rate; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Failure, Chronic; Male; Organ Size; Polycystic Kidney, Autosomal Dominant; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

One year survival of islet cell grafts has been reproducibly achieved under combination immune therapy including tacrolimus (TAC). However, the use of TAC causes beta-cell and renal toxicity. Because sirolimus (SIR) monotherapy was successful in kidney transplantation under antithymocyte globulin (ATG), we undertook a pilot study comparing SIR monotherapy with SIR-TAC combination therapy.. Nonuremic type 1 diabetics received a cultured beta-cell graft under ATG and were randomly assigned to SIR or SIR-TAC-maintenance therapy; a second graft was implanted during posttransplantation month 3 without ATG. The planned number of patients per group (n=10) was reduced to five in view of the observed side effects.. At posttransplant month 6, three SIR-patients had lost graft function and two presented marginal function; among SIR-TAC-patients, there were two early graft failures but three became insulin-independent. These three patients maintained metabolically relevant function (C-peptide >1 ng/ml and coefficient of variation fasting glycemia <25%) for more than 2 years but low-dose insulin therapy was needed from 8, 18, and 26 months posttransplant; this was still the case in two of them after reducing and stopping TAC dose. In both groups, incapacitating adverse events were attributed to sirolimus requiring its discontinuation in 4 of 10 patients; in the 3 patients with pretransplant microalbuminuria, macroalbuminuria developed which resolved when sirolimus was stopped.. SIR monotherapy is not sufficient to suppress rejection after transplantation under ATG, but it can maintain survival of established beta-cell grafts. However, the risk for a SIR-induced proteinuria remains a concern.

Topics: Adult; Albuminuria; Autoantibodies; C-Peptide; Cell Transplantation; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Lymphocyte Count; Male; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus

Anti-Thy1.1 transgenic mice develop glomerular lesions that mimic collapsing focal segmental glomerulosclerosis (FSGS) in humans with collapse of the glomerular tuft and marked hyperplasia of the parietal epithelial cells (PECs). Immunostaining of phosphor-S6 ribosomal protein (pS6RP) revealed high mTOR activity in PECs of the FSGS lesions of these mice. In this study we questioned whether the mTOR inhibitor rapamycin (sirolimus) could attenuate the development and progression of glomerulosclerotic lesions in the anti-Thy1.1 transgenic mice. We observed reduced mTOR signalling and proliferation in human parietal epithelial cells after rapamycin treatment. Experiments with anti-Thy1.1. mice showed that early treatment with sirolimus reduced the development of glomerular lesions and glomerular cell proliferation at day 4. Levels of albuminuria, podocyte injury and podocyte number were similar in the sirolimus and vehicle treated groups. The initial beneficial effects of sirolimus treatment were not observed at day 7. Late sirolimus treatment did not reduce albuminuria or the progression of glomerulosclerosis. Taken together, rapamycin attenuated PEC proliferation and the formation of early FSGS lesions in experimental FSGS and reduced human PEC proliferation in vitro. However, the initial inhibition of PEC proliferation did not translate into a decline of albuminuria nor in a sustained reduction in sclerotic lesions.

Topics: Albuminuria; Animals; Cell Proliferation; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Sclerosis; Signal Transduction; Sirolimus; Thy-1 Antigens; TOR Serine-Threonine Kinases

The aim was to explore the effects of rapamycin on autophagy and injury of podocytes in streptozocin (STZ)-induced type 1 diabetic mice, and its role in delaying progression of diabetic nephropathy. In this study, male Balb/c mice were divided into three groups: control (n = 12), STZ-induced diabetic (n = 12), and rapamycin-treated diabetic (DM + Rapa) (n = 12), which received intraperitoneal injection of rapamycin (2 mg/kg/48 h) after induction of DM. Levels of urinary albumin (UA), blood urea nitrogen, serum creatinine, and kidney weight/body weight were measured at week 12. Renal pathologic changes, number of podocytes autophagy, and organelles injury were investigated by PAS staining, transmission electron microscopy, and immunofluorescence staining, respectively. Western blot was performed to determine the expression of LC3 (a podocyte autophagy marker), phosphorylated mammalian target of rapamycin, p-p70S6K, bax, and caspase-3 protein. Podocytes count was evaluated by immunofluorescence staining and Wilms tumor 1 immunohistochemistry, and Western blot of nephrin and podocin. The results indicated that rapamycin could reduce the kidney weight/body weight and UA secretion. It could alleviate podocyte foot process fusion, glomerular basement membrane thickening, and matrix accumulation, and increase the number of autophagosomes, and LC3-expressing podocytes. Down-regulation of bax and caspase-3 protein, and up-regulation of nephrin and podocin protein were observed in the glomeruli of diabetic mice after administration of rapamycin. In conclusion, rapamycin can ameliorate renal injury in diabetic mice by increasing the autophagy activity and inhibition of apoptosis of podocytes.

Topics: Albuminuria; Animals; Autophagy; bcl-2-Associated X Protein; Biomarkers; Blood Urea Nitrogen; Caspase 3; Cytoprotection; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice, Inbred BALB C; Microtubule-Associated Proteins; Podocytes; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Time Factors

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists and mammalian target of rapamycin (mTOR) inhibitors share mechanisms concerning cell growth and reduction of extracellular matrix accumulation. The purpose of this study was to evaluate the potential synergistic effect of this combination on diabetic kidney disease in rats.. Diabetes was induced by streptozotocin in 42 male Sprague-Dawley rats. Sixteen weeks after diabetes induction, animals were divided into four groups: diabetic animals without intervention (D), diabetic animals with administration of sirolimus (D+SRL), diabetic animals with administration of rosiglitazone (D+RGT), and diabetic animals with administration of sirolimus and rosiglitazone (D+SRL+RGT).. At a 30-day follow up, diabetic rats showed higher kidney weight, mean glomerular volume, mesangial expansion and albuminuria compared with non-diabetic rats. mTOR downstream proteins, p-T389-S6K and p-T37/46-4EBP1, were higher in diabetic than non-diabetic kidneys, whereas p-S473-AKT was not, suggesting that hyperglycemia mainly activated the mTORC1 pathway in vivo. Moreover, the catalytic subunit of protein phosphatase 2A (PP2Ac) was down-regulated in the diabetic kidney. Sirolimus inhibited the mTORC1 pathway, while the PPAR-gamma agonist rosiglitazone enhanced PP2Ac and reduced p70S6K. Both drugs were associated with a reduction in albuminuria, renal enlargement and mesangial expansion, but without any improvement in glycemic control. Sirolimus and rosiglitazone in combination down-regulated the mTORC1 pathway and over-activated PP2Ac in diabetic kidney. This effect may account for the synergistic reduction of renal hypertrophy, albuminuria and renal TGF-beta1 observed in diabetic rats treated with SRL+RGT.. The combination of sirolimus and rosiglitazone is renoprotective with respect to diabetic nephropathy.

Topics: Albuminuria; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Down-Regulation; Drug Synergism; Drug Therapy, Combination; Hypoglycemic Agents; Immunosuppressive Agents; Male; Protein Phosphatase 2; Rats; Rats, Sprague-Dawley; Rosiglitazone; Sirolimus; Thiazolidinediones; Transcription Factors; Transforming Growth Factor beta1

Rapamycin is an immunosuppressive drug with potent antifibrotic activity. We evaluated the effect of rapamycin on murine adriamycin nephropathy, a model of progressive glomerulosclerosis and tubulointerstitial fibrosis.. Adriamycin nephropathy was induced in Balb/c mice by a single intravenous injection of adriamycin. The mice were treated orally with either saline or rapamycin, beginning at the time of adriamycin injection or rapamycin starting 1 week after adriamycin injection. The mice were sacrificed 6 weeks after adriamycin injection.. Saline-treated mice developed massive proteinuria and impaired renal function. Kidney sections from saline-treated mice showed marked focal segmental glomerulosclerosis, tubular dilation with protein cast deposition, interstitial fibrosis, and numerous infiltrating macrophages and T lymphocytes. The intrarenal expression of Collagen I and RANTES was also increased. In contrast, both groups of rapamycin-treated mice had markedly reduced proteinuria and preserved renal function, with only mild histological abnormalities. The intrarenal expression of Collagen I and RANTES was reduced, concomitant with a significant reduction in interstitial inflammatory cell infiltration.. Rapamycin is effective in attenuating the glomerular and tubulointerstitial abnormalities in adriamycin nephropathy. The beneficial effects of rapamycin are mediated, at least in part, through reduced RANTES expression and inflammatory cell infiltration.

Topics: Albuminuria; Animals; Antibiotics, Antineoplastic; Body Weight; Chemokine CCL5; Collagen Type I; Disease Models, Animal; Doxorubicin; Fibrosis; Gene Expression; Glomerulosclerosis, Focal Segmental; Immunosuppressive Agents; Kidney; Male; Mice; Mice, Inbred BALB C; Severity of Illness Index; Sirolimus; Survival Rate

Ischemia reperfusion injury (IRI) has long-term sequelae on kidney allograft function. Early initiation of rapamycin can retard surgical wound healing and recovery from IRI. In contrast, rapamycin may paradoxically retard long-term fibrotic effects of kidney IRI. We, therefore, hypothesized that delayed initiation of rapamycin after kidney ischemia, started after the initial week of wound healing, would decrease the long-term inflammation and fibrosis caused by IRI. C57BL/6 male mice were subjected to either 45 or 60 minutes of unilateral kidney ischemia or a sham operation. Mice were given rapamycin (subcutaneous, 1.5 mg/kg/d) or vehicle starting at 1 week after IRI surgery for 3 weeks. Urine albumin excretion, kidney histology, and kidney cytokine proteins were examined at 4 weeks after surgery. The 3-week treatment course of rapamycin significantly reduced body weight gain in all 3 groups and reduced postischemic kidney weight in both the 45- and 60-minute ischemia groups, but unexpectedly increased urine albumin excretion in all rapamycin-treated sham or IRI mice compared with vehicle-treated mice. Rapamycin treatment showed minimal effects on postischemic kidney fibrosis with variable effects on various cytokine/chemokine protein expressions, namely, decreasing interleukin (IL)-1alpha, IL-6, tumor necrosis factor (TNF)-alpha, and regulated on activation normal T cell expressed and secreted (RANTES) while increasing IL-4, keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP-1alpha), and IL-10 in the ischemic kidney. These data demonstrated that rapamycin reduced mouse body weight and ischemic kidney weight, while increasing urinary albumin excretion. Delayed initiation of rapamycin after IRI had a minimal effect on renal fibrosis and mixed effects on proinflammatory mediator production. These data do not support delayed initiation of rapamycin after IRI to attenuate IRI-induced progressive fibrosis and inflammation, and They raise further caution regarding rapamycin and albuminuria.

Topics: Albuminuria; Animals; Body Weight; Cytokines; Fibrosis; Immunosuppressive Agents; Injections, Subcutaneous; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Organ Size; Reperfusion Injury; Sirolimus; Weight Gain

Chronic allograft nephropathy (CAN) is a major cause of progressive renal failure in kidney transplant recipients. Its etiology is multifactorial and can be due to immunologic or nonimmunologic conditions including calcineurin inhibitor (CNI) toxicity.. To evaluate the effect of conversion from CNIs to everolimus in kidney transplant recipients with CAN.. In this 12-month pilot study in renal transplant recipients with biopsy-proved CAN, therapy was changed to an everolimus-based immunosuppression regimen. Cyclosporine or tacrolimus dosage was reduced by 80% (group 1, n = 10) or discontinued (group 2, n = 10). Mycophenolate mofetil or azathioprine were withdrawn in group 1, whereas both agents were maintained in group 2. All patients received prednisone.. Twenty renal allograft recipients switched to an everolimus-based regimen, and patients were followed up for a mean (SD) of 12 (0.1) months. Baseline and end-of-study data were as follows: serum creatinine concentration, 1.27 (0.35) mg/dL vs 1.24 (0.4) mg/dL in group 1, and 1.27 mg/dL (0.36) vs 1.25 (0.3) mg/dL in group 2 (difference not significant); and estimated glomerular filtration rate, 72.4 (19.86) mL/min vs 76.26 (22.69) mL/min in group 1 (not significant), and 66.2 (12.95) mL/min vs 66.2 (13.73) mL/min in group 2 (not significant). One patient in group 1 experienced an acute rejection episode (Banff grade Ib), and 2 patients in group 1 and 1 patient in group 2 demonstrated borderline changes, all associated with everolimus blood concentration less than 3 ng/mL.. Reduction or withdrawal of CNI and introduction of everolimus may be useful to slow the rate of loss of renal function in patients with CAN.

Topics: Adult; Albuminuria; Cadaver; Calcineurin Inhibitors; Creatinine; Cyclosporine; Drug Administration Schedule; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Prospective Studies; Random Allocation; Sirolimus; Time Factors; Tissue Donors

Rapamycin is a potent immunosuppressive drug with proven efficacy in rejection prophylaxis in solid organ transplantation. By virtue of its immunosuppressive properties, rapamycin might also be useful in the treatment of autoimmune diseases. The aim of this study was to determine the effect of rapamycin on the severity of established nephritis in lupus-prone New Zealand Black/White F(1) (NZB/W F(1)) mice.. Six-month-old female NZB/W F(1) mice with active nephritis (albuminuria >100 mg/dL) were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 4 months. The effect of rapamycin on the severity of nephritis was evaluated by clinical manifestations, biochemical parameters, renal histology, immunohistochemistry and semi-quantitative gene expression studies.. Treatment with rapamycin significantly decreased albuminuria, improved survival, diminished splenomegaly, preserved renal function and reduced serum anti-dsDNA antibody levels. Kidney sections from saline-treated mice revealed marked mesangial proliferation, tubular dilation with intra-tubular protein cast deposition and leukocytic infiltration of the interstitium. The rapamycin-treated mice, in contrast, had relatively mild histological changes in their kidneys. Rapamycin treatment also significantly reduced the amount of immune complex deposition in the glomeruli, suppressed the interstitial infiltration by T-cells, B-cells and macrophages as well as down-regulated the intra-renal expression of RANTES.. We conclude that rapamycin is effective in attenuating the severity of established nephritis in NZB/W F(1) mice. The beneficial effects of rapamycin are mediated, at least in part, through inhibition of lymphoproliferation, reduced RANTES expression and decreased inflammatory cell infiltration in the kidneys. Rapamycin could be of therapeutic value in the treatment of human lupus nephritis.

Topics: Albuminuria; Animals; Autoimmunity; Chemokine CCL5; Female; Immunosuppressive Agents; Kidney; Lupus Nephritis; Mice; Mice, Inbred NZB; Nephritis; Sirolimus; Splenomegaly

Tight glycemic control can reduce progression of diabetic nephropathy (DN) while the histological changes may regress after pancreas transplantation. Clinical islet transplantation (CIT) can restore euglycemia but the effects of CIT and concomitant immunosuppression on renal function are not known. Renal function (modification of diet in renal disease estimated glomerular filtration rate [GFR]) is reported in 41 type 1 diabetes subjects followed for 29.8 (6-57) months after CIT who received sirolimus and tacrolimus. HbA(1c) improved by 3 months (6.1 +/- 0.5 vs. 8.1 +/- 1.3%, p < 0.001) and was sustained. Over 4 years estimated GFR (eGFR) declined (repeated measures ANOVA: p = 0.0011). The median rate of change in eGFR was -0.39 mL/min/1.73 m(2)/month but was highly variable (range: +1.62 to -2.79 mL/min/1.73 m(2)/month). Progression of albuminuria was observed in ten individuals while regression of microalbuminuria was observed in only one (chi square = 22.51, df = 4, p = 0.0002). Despite improved glycemia, CIT and concomitant immunosuppression, was associated with a fall in eGFR and progression of albuminuria over 4 years of observation. The rate of decline in eGFR was extremely variable and difficult to predict. The risk of progressive nephrotoxicity with decline in eGFR should be discussed with prospective CIT candidates and the risk: benefit ratio carefully considered in individuals with pre-existing renal impairment.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Immunosuppression Therapy; Islets of Langerhans Transplantation; Kidney; Male; Middle Aged; Sirolimus; Tacrolimus

Topics: Albuminuria; Blood Glucose; Diabetes Mellitus, Type 1; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Sirolimus; Tacrolimus

Recent studies suggested the involvement of the Akt/mammalian target of rapamycin (mTOR) pathway in the pathogenesis of diabetic nephropathy. The effect of mTOR blockade by rapamycin in diabetic nephropathy was investigated, but in vivo study of rapamycin treatment in the course of early diabetes is still insufficient. This study was designed to determine the therapeutic effects of rapamycin on diabetic nephropathy at an early stage.. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and rapamycin (1 mg/kg) was administered by daily gavage for 4 weeks. Renal structural changes and some factors involved in the early pathogenesis of diabetic nephropathy were tested. The activation level of the Akt/mTOR pathway was also determined.. Rapamycin treatment reduced albuminuria, glomerular enlargement, glomerular basement membrane thickening, renal macrophage recruitment, and levels of renal mRNA expression of proliferating cell nuclear antigen, transforming growth factor-beta1, vascular endothelial growth factor, and monocyte chemoattractant protein-1 without change in blood glucose level and blood pressure in experimental diabetic rats. In addition, treatment with rapamycin also down-regulated the enhanced levels of renal p-Akt, phospho-p70S6 kinase, and phospho-ribosomal S6 protein in diabetic rats.. Rapamycin treatment can prevent the early renal structural changes of diabetes in experimental rats, and thus halt the early steps of the development of diabetic nephropathy. mTOR blockade might be beneficial for the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glomerular Basement Membrane; Hypertrophy; Kidney; Kidney Glomerulus; Male; Protein Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 1; Female; Glomerulonephritis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Proteinuria; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

To evaluate the effects of oral rapamycin (RAPA), a macrolide immunosuppressant that has been shown to interfere with T cell activation events, on the course of spontaneous disease progression in the MRL/MpJ/lpr/lpr (MRL/l) mouse model of lupus.. RAPA treatment (6, 12, or 25 mg/kg 3 times per week) was evaluated by monitoring survival rates, autoantibody levels, and urinary albumin levels. Additionally, concanavalin A responsiveness, interleukin-2 (IL-2) production, lymphoid organ size, and histopathology were evaluated ex vivo.. RAPA prevented the typical rise in anti-double-stranded DNA antibody and urinary albumin levels and prolonged survival. Spleen and lymph node sizes were significantly decreased, inflammatory changes in the lung, liver, kidney, spleen, lymph node, and thymus were significantly reduced, and T cell mitogen-stimulated splenocyte proliferation and IL-2 production were restored.. Data from 3 independent experiments demonstrated that RAPA significantly reduced or prevented many pathologic features of lupus normally seen in the MRL/l mouse, and suggest that RAPA may be useful as a therapeutic agent in SLE in humans.

Topics: Administration, Oral; Albuminuria; Animals; Antibodies, Antinuclear; Cyclosporine; Female; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mice; Mice, Mutant Strains; Polyenes; Sirolimus; Survival Analysis